Method for preparing 3-halo-4,5-dihydro-1H-pyrazoles

ABSTRACT

This invention relates to a method for preparing 3-halo-4,5-dihydro-1H-pyrazole compound of Formula (I), comprising contacting with HX 1  a different 4,5-dihydro-1H-pyrazole compound of Formula (II), wherein X 1  is halogen and L, R, k and X 2  are as defined in the disclosure. This invention also discloses preparation of compounds of Formula (III) wherein X 1 , R 3 , R 6 , R 7 , R 8a , R 8b , and n are as defined in the disclosure

This application represents a national filing under 35 USC 371 ofInternational Application No. PCT/US2003/023820 filed Jul. 29, 2003 andclaims priority of U.S. Provisional Application No. 60/446,451 filedFeb. 11, 2003 and U.S. Provisional Application No. 60/400,356 filed Jul.31, 2002.

BACKGROUND OF THE INVENTION

A need exists for additional methods to prepare3-halo-4,5-dihydro-1H-pyrazoles. Such compounds include usefulintermediates for the preparation of crop protection agents,pharmaceuticals and other fine chemicals.

Several methods have been reported for the preparation of3-halo-4,5-dihydro-1H-pyrazoles. For example, J. P. Chupp, J.Heterocyclic Chem. 1994, 31, 1377-1380 reports the preparation of a3-chloro-4,5-dihydro-1H-pyrazole by contacting the correspondingoxo-pyrazolidine with phosphorus oxychloride. M. V. Gorelik et al.,Journal of Organic Chemistry U.S.S.R. 1985, 21, 773-781 (Englishlanguage translation of Zhurnal Organicheskoi Khimil 1985, 21(4),851-859) discloses the preparation of 3-chloro-4,5-dihydro-1H-pyrazolesby way of diazonium salt intermediates prepared from the corresponding3-amino-4,5-dihydro-1H-pyrazoles. K. K. Bach et al., Tetrahedron 1994,50(25), 7543-7556 discloses the preparation of a3-chloro-4,5-dihydro-1H-pyrazole by dipolar cycloaddition of an acrylateester with a hydrazidoyl chloride intermediate formed by decarboxylativechlorination of a hydrazone of glyoxylic acid using N-chlorosuccinimide.The need remains for alternative methods, particularly those of broadchemical structure generality and which use relatively low cost reagentscommercially available in industrial quantities.

SUMMARY OF THE INVENTION

This invention relates to a method for preparing a3-halo-4,5-dihydro-1H-pyrazole compound of Formula I

wherein L is an optionally substituted carbon moiety;

-   -   each R is independently selected from optionally substituted        carbon moieties;    -   k is an integer from 0 to 4;    -   and X¹ is halogen.

The method comprises contacting a 4,5-dihydro-1H-pyrazole compound ofFormula II

wherein X² is OS(O)_(m)R¹, OP(O)_(p)(OR²)₂ or a halogen other than X¹;

-   -   m is 1 or 2;    -   p is 0 or 1;    -   R¹ is selected from alkyl and haloalkyl; and phenyl optionally        substituted with from 1 to 3 substituents selected from alkyl        and halogen; and    -   each R² is independently selected from alkyl and haloalkyl; and        phenyl optionally substituted with from 1 to 3 substituents        selected from alkyl and halogen;        with a compound of the formula HX¹ in the presence of a suitable        solvent.

This invention also relates to a method of preparing a compound ofFormula III,

wherein

X¹ is halogen;

-   -   each R³ is independently C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄        alkynyl, C₃-C₆ cycloalkyl, C₁-C₄ haloalkyl, C₂-C₄ haloalkenyl,        C₂-C₄ haloalkynyl, C₃-C₆ halocycloalkyl, halogen, CN, NO₂, C₁-C₄        alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,        C₁-C₄ alkylsulfonyl, C₁-C₄ alkylamino, C₂-C₈ dialkylamino, C₃-C₆        cycloalkylamino, (C₁-C₄ alkyl)(C₃-C₆ cycloalkyl)amino, C₂-C₄        alkylcarbonyl, C₂-C₆ alkoxycarbonyl, C₂-C₆ alkylaminocarbonyl,        C₃-C₈ dialkylaminocarbonyl or C₃-C₆ trialkylsilyl;    -   Z is N or CR⁵;    -   R⁵ is H or R³;    -   R⁶ is CH₃, F, Cl or Br;    -   R⁷ is F, Cl, Br, I or CF₃;    -   R^(8a) is C₁-C₄alkyl;    -   R^(8b) is H or CH₃; and    -   n is an integer from 0 to 3 using a compound of Formula Ia

-   -   wherein R⁴ is H or an optionally substituted carbon moiety.        This method is characterized by preparing the compound of        Formula Ia (i.e. a subgenus of Formula I) by the method as        indicated above.

DETAILED DESCRIPTION OF THE INVENTION

In the recitations herein, the term “carbon moiety” refers to a radicalin which a carbon atom is connected to the backbone of the4,5-dihydro-1H-pyrazole ring. As the carbon moieties L and R (includingR⁴) are substituents separated from the reaction center, they canencompass a great variety of carbon-based groups preparable by modernmethods of synthetic organic chemistry. The method of this invention isgenerally applicable to a wide range of starting compounds of Formula Iand product compounds of Formula II. One skilled in the art willrecognize that certain groups are sensitive to hydrogen halides and maybe transformed under the reaction conditions. One skilled in the artwill also recognize that certain groups are basic and can form saltswith hydrogen halides, and thus the method of this invention can requireadditional hydrogen halide.

“Carbon moiety” thus includes alkyl, alkenyl and alkynyl, which can bestraight-chain or branched. “Carbon moiety” also includes carbocyclicand heterocyclic rings, which can be saturated, partially saturated, orcompletely unsaturated. Furthermore, unsaturated rings can be aromaticif Hückel's rule is satisfied. The carbocyclic and heterocyclic rings ofa carbon moiety can form polycyclic ring systems comprising multiplerings connected together. The term “carbocyclic ring” denotes a ringwherein the atoms forming the ring backbone are selected only fromcarbon. The term “heterocyclic ring” denotes a ring wherein at least oneof the ring backbone atoms is other than carbon. “Saturated carbocyclic”refers to a ring having a backbone consisting of carbon atoms linked toone another by single bonds; unless otherwise specified, the remainingcarbon valences are occupied by hydrogen atoms. The term “aromatic ringsystem” denotes fully unsaturated carbocycles and heterocycles in whichat least one ring in a polycyclic ring system is aromatic. Aromaticindicates that each of ring atoms is essentially in the same plane andhas a p-orbital perpendicular to the ring plane, and in which (4n+2)πelectrons, when n is 0 or a positive integer, are associated with thering to comply with Hückel's rule. The term “aromatic carbocyclic ringsystem” includes fully aromatic carbocycles and carbocycles in which atleast one ring of a polycyclic ring system is aromatic. The term“nonaromatic carbocyclic ring system” denotes fully saturatedcarbocycles as well as partially or fully unsaturated carbocycleswherein none of the rings in the ring system are aromatic. The terms“aromatic heterocyclic ring system” and “heteroaromatic ring” includefully aromatic heterocycles and heterocycles in which at least one ringof a polycyclic ring system is aromatic. The term “nonaromaticheterocyclic ring system” denotes fully saturated heterocycles as wellas partially or fully unsaturated heterocycles wherein none of the ringsin the ring system are aromatic. The term “aryl” denotes a carbocyclicor heterocyclic ring or ring system in which at least one ring isaromatic, and the aromatic ring provides the connection to the remainderof the molecule.

The carbon moieties specified for L, R and R⁴ are optionallysubstituted. The term “optionally substituted” in connection with thesecarbon moieties refers to carbon moieties that are unsubstituted or haveat least one non-hydrogen substituent. Illustrative optionalsubstituents include alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl,hydroxycarbonyl, formyl, alkylcarbonyl, alkenylcarbonyl,alkynylcarbonyl, alkoxycarbonyl, hydroxy, alkoxy, alkenyloxy, alknyloxy,cycloalkoxy, aryloxy, alkylthio, alkenylthio, alkynylthio,cycloalkylthio, arylthio, alkylsulfinyl, alkenylsulfinyl,alkynylsulfinyl, cycloalkylsulfinyl, arylsulfinyl, alkylsulfonyl,alkenylsulfonyl, alkynylsulfonyl, cycloalkylsulfonyl, arylsulfonyl,amino, alkylamino, alkenylamino, alkynylamino, arylamino, aminocarbonyl,alkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl,arylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl,alkynylaminocarbonyl, arylaminocarbonyloxy, alkoxycarbonylamino,alkenyloxycarbonylamino, alkynyloxycarbonylamino andaryloxy-carbonylamino, each further optionally substituted; and halogen,cyano and nitro. The optional further substituents are independentlyselected from groups like those illustrated above for the substituentsthemselves to give additional substituent groups for L, R and R⁴ such ashaloalkyl, haloalkenyl and haloalkoxy. As a further example, alkylaminocan be further substituted with alkyl, giving dialkylamino. Thesubstituents can also be tied together by figuratively removing one ortwo hydrogen atoms from each of two substituents or a substituent andthe supporting molecular structure and joining the radicals to producecyclic and polycyclic structures fused or appended to the molecularstructure supporting the substituents. For example, tying togetheradjacent hydroxy and methoxy groups attached to, for example, a phenylring gives a fused dioxolane structure containing the linking group—O—CH₂—O—. Tying together a hydroxy group and the molecular structure towhich it is attached can give cyclic ethers, including epoxides.Illustrative substituents also include oxygen, which when attached tocarbon forms a carbonyl function. Similarly, sulfur when attached tocarbon forms a thiocarbonyl function. Within a carbon moiety L or R,tying together substituents can form cyclic and polycyclic structures.Also illustrative of carbon moieties L and R are embodiments wherein atleast two R moieties, or the L moiety and at least one R moiety, arecontained in the same radical (i.e., a ring system is formed). As the4,5-dihydropyrazole moiety constitutes one ring, two vicinallypositioned R moieties, or L and R moieties, contained in the sameradical would result in a fused bicyclic or polycyclic ring system. Twogeminally positioned R moieties contained in the same radical wouldresult in a spiro ring system.

As referred to herein, “alkyl”, used either alone or in compound wordssuch as “alkylthio” or “haloalkyl” includes straight-chain or branchedalkyl, such as, methyl, ethyl, n-propyl, i-propyl, or the differentbutyl, pentyl or hexyl isomers. The term “1-2 alkyl” indicates that oneor two of the available positions for that substituent may be alkylwhich are independently selected. “Alkenyl” includes straight-chain orbranched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and thedifferent butenyl, pentenyl and hexenyl isomers. “Alkenyl” also includespolyenes such as 1,2-propadienyl and 2,4-hexadienyl. “Alkynyl” includesstraight-chain or branched alkynes such as ethynyl, 1-propynyl,2-propynyl and the different butynyl, pentynyl and hexynyl isomers.“Alkynyl” can also include moieties comprised of multiple triple bondssuch as 2,5-hexadiynyl. “Alkoxy” includes, for example, methoxy, ethoxy,n-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxyisomers. “Alkenyloxy” includes straight-chain or branched alkenyloxymoieties. Examples of “alkenyloxy” include H₂C═CHCH₂O, (CH₃)₂C═CHCH₂O,(CH₃)CH═CHCH₂O, (CH₃)CH═C(CH₃)CH₂O and CH₂═CHCH₂CH₂O. “Alkynyloxy”includes straight-chain or branched alkynyloxy moieties. Examples of“alkynyloxy” include HC≡CCH₂O, CH₃C≡CCH₂O and CH₃C≡CCH₂CH₂O. “Alkylthio”includes branched or straight-chain alkylthio moieties such asmethylthio, ethylthio, and the different propylthio, butylthio,pentylthio and hexylthio isomers. “Alkylsulfinyl” includes bothenantiomers of an alkylsulfinyl group. Examples of “alkylsulfinyl”include CH₃S(O), CH₃CH₂S(O), CH₃CH₂CH₂S(O), (CH₃)₂CHS(O) and thedifferent butylsulfinyl, pentylsulfinyl and hexylsulfinyl isomers.Examples of “alkylsulfonyl” include CH₃S(O)₂, CH₃CH₂S(O)₂,CH₃CH₂CH₂S(O)₂, (CH₃)₂CHS(O)₂ and the different butylsulfonyl,pentylsulfonyl and hexylsulfonyl isomers. “Alkylamino”, “alkenylthio”,“alkenylsulfinyl”, “alkenylsulfonyl”, “alkynylthio”, “alkynylsulfinyl”,“alkynylsulfonyl”, and the like, are defined analogously to the aboveexamples. Examples of “alkylcarbonyl” include C(O)CH₃, C(O)CH₂CH₂CH₃ andC(O)CH(CH₃)₂. Examples of “alkoxycarbonyl” include CH₃OC(═O),CH₃CH₂OC(═O), CH₃CH₂CH₂OC(═O), (CH₃)₂CHOC(═O) and the different butoxy-or pentoxycarbonyl isomers. “Cycloalkyl” includes, for example,cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term“cycloalkoxy” includes the same groups linked through an oxygen atomsuch as cyclopentyloxy and cyclohexyloxy. “Cycloalkylamino” means theamino nitrogen atom is attached to a cycloalkyl radical and a hydrogenatom and includes groups such as cyclopropylamino, cyclobutylamino,cyclopentylammo and cyclohexylamino. “(Alkyl)(cycloalkyl)amino” means acycloalkylamino group where the hydrogen atom is replaced by an alkylradical; examples include groups such as (methyl)(cyclopropyl)amino,(butyl)(cyclobutyl)amino, (propyl)cyclopentylamino,(methyl)cyclohexylamino and the like. “Cycloalkenyl” includes groupssuch as cyclopentenyl and cyclohexenyl as well as groups with more thanone double bond such as 1,3- and 1,4-cyclohexadienyl.

The term “halogen”, either alone or in compound words such as“haloalkyl”, includes fluorine, chlorine, bromine or iodine. The term“1-2 halogen” indicates that one or two of the available positions forthat substituent may be halogen which are independently selected.Further, when used in compound words such as “haloalkyl”, said alkyl maybe partially or fully substituted with halogen atoms which may be thesame or different. Examples of “haloalkyl” include F₃C, ClCH₂, CF₃CH₂and CF₃CCl₂.

The total number of carbon atoms in a substituent group is indicated bythe “C_(i)-C_(j)” prefix where i and j are, for example, numbers from 1to 3; e.g., C₁-C₃ alkyl designates methyl through propyl.

Although there is no definite limit to the sizes of Formulae I and IIsuitable for the processes of the invention, typically Formula IIcomprises 4-100, more commonly 4-50, and most commonly 4-25 carbonatoms, and 3-25, more commonly 3-15, and most commonly 3-10 heteroatoms.The heteroatoms are commonly selected from halogen, oxygen, sulfur,nitrogen and phosphorus. Two heteroatoms in Formulae I and II are thedihydropyrazole ring nitrogen atoms; X¹ is halogen, and X² will containat least one heteroatom.

Although there is no definite limit to the size of L and R (includingR⁴), optionally substituted alkyl moieties in L and R (including R⁴)commonly include 1 to 6 carbon atoms, more commonly 1 to 4 carbon atomsand most commonly 1 to 2 carbon atoms in the alkyl chain. Optionallysubstituted alkenyl and alkynyl moieties in L and R (including R⁴)commonly include 2 to 6 carbon atoms, more commonly 2 to 4 carbon atomsand most commonly 2 to 3 carbon atoms in the alkenyl or alkynyl chain.

Also, there is no definite limit to the size of the groups listed for R¹and R² but alkyl, including derivatives such as alkoxy and haloalkyl, iscommonly C₁-C₆, more commonly C₁-C₄, and most commonly C₁-C₂.

As indicated above, the carbon moieties L, R and R⁴ may be (amongothers) an aromatic ring or ring system. Examples of aromatic rings orring systems include a phenyl ring, 5- or 6-membered heteroaromaticrings aromatic 8-, 9- or 10-membered fused carbobicyclic ring systemsand aromatic 8-, 9- or 10-membered fused heterobicyclic ring systemswherein each ring or ring system is optionally substituted. The term“optionally substituted” in connection with these L and R carbonmoieties refers to carbon moieties which are unsubstituted or have atleast one non-hydrogen substituent These carbon moieties may besubstituted with as many optional substituents as can be accommodated byreplacing a hydrogen atom with a non-hydrogen substituent on anyavailable carbon or nitrogen atom. Commonly, the number of optionalsubstituents (when present) ranges from one to four. An example ofphenyl optionally substituted with from one to four substituents is thering illustrated as U-1 in Exhibit 1, wherein R^(v) is any non-hydrogensubstituent and r is an integer from 0 to 4. Examples of aromatic 8-, 9-or 10-membered fused carbobicyclic ring systems optionally substitutedwith from one to four substituents include a naphthyl group optionallysubstituted with from one to four substituents illustrated as U-85 and a1,2,3,4-tetrahydronaphthyl group optionally substituted with from one tofour substituents illustrated as U-86 in Exhibit 1, wherein R^(v) is anysubstituent and r is an integer from 0 to 4. Examples of 5- or6-membered heteroaromatic rings optionally substituted with from one tofour substituents include the rings U-2 through U-53 illustrated inExhibit 1 wherein R^(v) is any substituent and r is an integer from 1 to4. Examples of aromatic 8-, 9- or 10-membered fused heterobicyclic ringsystems optionally substituted with from one to four substituentsinclude U-54 through U-84 illustrated in Exhibit 1 wherein R^(v) is anysubstituent and r is an integer from 0 to 4. Other examples of L and Rinclude include a benzyl group optionally substituted with from one tofour substituents illustrated as U-87 and a benzoyl group optionallysubstituted with from one to four substituents illustrated as U-88 inExhibit 1, wherein R^(v) is any substituent and r is an integer from 0to 4.

Although R^(v) groups are shown in the structures U-1 through U-85, itis noted that they do not need to be present since they are optionalsubstituents. The nitrogen atoms that require substitution to fill theirvalence are substituted with H or R^(v). Note that some U groups canonly be substituted with less than 4 R^(v) groups (e.g. U-14, U-15, U-18through U-21 and U-32 through U-34 can only be substituted with oneR^(v)). Note that when the attachment point between R^(v))_(r) and the Ugroup is illustrated as floating, (R^(v))_(r) can be attached to anyavailable carbon atom or nitrogen atom of the U group. Note that whenthe attachment point on the U group is illustrated as floating, the Ugroup can be attached to the remainder of Formulae I and II through anyavailable carbon of the U group by replacement of a hydrogen atom.

As indicated above, the carbon moieties L, R and R⁴ may be (amongothers) saturated or partially saturated carbocyclic and heterocyclicrings, which can be further optionally substituted. The term “optionallysubstituted” in connection with these L and R carbon moieties refers tocarbon moieties which are unsubstituted or have at least onenon-hydrogen substituent. These carbon moieties may be substituted withas many optional substituents as can be accommodated by replacing ahydrogen atom with a non-hydrogen substituent on any available carbon ornitrogen atom. Commonly, the number of optional substituents (whenpresent) ranges from one to four. Examples of saturated or partiallysaturated carbocyclic rings include optionally substituted C₃-C₈cycloalkyl and optionally substituted C₃-C₈ cycloalkyl. Examples ofsaturated or partially saturated heterocyclic rings include 5- or6-membered nonaromatic heterocyclic rings optionally including one ortwo ring members selected from the group consisting of C(═O), SO orS(O)₂, optionally substituted. Examples of such L and R carbon moietiesinclude those illustrated as G-1 through G-35 in Exhibit 2. Note thatwhen the attachment point on these G groups is illustrated as floating,the G group can be attached to the remainder of Formulae I and IIthrough any available carbon or nitrogen of the G group by replacementof a hydrogen atom. The optional substituents can be attached to anyavailable carbon or nitrogen by replacing a hydrogen atom (saidsubstituents are not illustrated in Exhibit 2 since they are optionalsubstituents). Note that when G comprises a ring selected from G-24through G-31, G-34 and G-35, Q² may be selected from O, S, NH orsubstituted N.

It is noted that the L, R and R⁴ carbon moieties may be optionallysubstituted. As noted above, L and R carbon moieties may commonlycomprise, among other groups, a U group or a G group further optionallysubstituted with from one to four substituents. Thus the L and R carbonmoieties may comprise a U group or a G group selected from U-1 throughU-88 or G-1 through G-35, and further substituted with additionalsubstituents including one to four U or G groups (which may be the sameor different) with both the core U or G group and substituent U or Ggroups optionally further substituted. Of particular note are L carbonmoieties comprising a U group optionally substituted with from one tothree additional substituents. For example, L can be the group U-41.

As shown in Scheme 1, according to the method of this invention a4,5-dihydro-1H-pyrazole of Formula II in contacted with HX¹ to form adifferent 3-halo-4,5-dihydro-1H-pyrazole compound of Formula I.

-   -   wherein L, R, X¹, X² and k are as defined in the Summary of the        Invention.        The reaction is conducted in a suitable solvent. For best        results the solvent should be non-nucleophilic, relatively inert        to HX¹ and capable of dissolving the compound of Formula II.        Suitable solvents include dibromomethane, dichloromethane,        acetic acid, ethyl acetate and acetonitrile. The reaction can be        conducted at or near atmospheric pressure or above atmospheric        pressure in a pressure vessel. The HX¹ starting material can be        added in the form of a gas to the reaction mixture containing        the Formula II compound and solvent. When X² in the compound of        Formula II is a halogen such as Cl, the reaction is preferably        conducted in a way such that the HX² generated by the reaction        is removed by sparging or other suitable means. Alternatively,        the HX¹ starting material can be first dissolved in an inert        solvent in which it is highly soluble (such as acetic acid)        before contacting with the compound of Formula II either neat or        in solution. Also when X² in the compound of Formula II is a        halogen such as Cl, substantially more than one equivalent of        HX¹ (e.g., 4 to 10 equivalents) is typically needed depending        upon the level of conversion desired. One equivalent of HX¹ can        provide high conversion when X² is OS(O)_(m)R¹ or        OP(O)_(p)(OR²)₂, but when the compound of Formula II comprises        at least one basic function (e.g., a nitrogen-containing        heterocycle), more than one equivalent is HX¹ is typically        needed. The reaction can be conducted between about 0 and 100°        C., most conveniently near ambient temperature (e.g., about        10-40° C.), and most preferably between about 20 and 30° C.        Addition of a Lewis acid catalyst (e.g., aluminum bromide for        preparing Formula I wherein X¹ is Br) can facilitate the        reaction. The product of Formula I is isolated by the usual        methods known to those skilled in the art, including extraction,        distillation and crystallization.

For the method of this invention, preferred starting compounds includecompounds of Formula II wherein m is 2 and p is 1. Also preferred arestarting compounds of Formula II wherein X² is halogen or OS(O)_(m)R¹(especially where m is 2). Further preferred are starting compounds ofFormula II wherein X² is Cl or OS(O)_(m)R¹, m is 2, and R¹ is C₁-C₆alkyl, CF₃ or phenyl optionally substituted with from 1 to 3substituents selected from C₁-C₄ alkyl, and more preferably R¹ is C₁-C₂alkyl, phenyl or 4-methylphenyl. Particularly preferred methods of thisinvention include those using a starting compound of Formula II whereinX² is Cl or OS(O)₂R¹, and R¹ is methyl, phenyl or 4-methylphenyl.Especially preferred method of this invention include those using astarting compound of Formula II wherein X² is Cl or OS(O)₂R¹, and R¹ isphenyl or 4-methylphenyl.

For the method of this invention, preferred product compounds includecompounds of Formula I wherein X¹ is Cl, Br or I. More preferred productcompounds include compounds of Formula I wherein X¹ is Cl or Br. Mostpreferred product compounds include compounds of Formula I wherein X¹ isBr. Particularly useful embodiments of the method of this inventioninclude the preparation of a compound of Formula I wherein X¹ is Cl orBr from a compound of Formula II wherein X² is OS(O)₂R¹, wherein R¹ is,for example, methyl, phenyl or 4-methylphenyl, more preferably phenyl or4-methylphenyl.

Preferred methods of this invention include the method wherein thestarting compound of Formula II is Formula IIa and the product compoundof Formula I is Formula Ia as shown in Scheme 2 below.

wherein X¹ and X² are as defined for Formulae I and II;

-   -   each R³ is independently C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄        alkynyl, C₃-C₆ cycloalkyl, C₁-C₄ haloalkyl, C₂-C₄ haloalkenyl,        C₂-C₄ haloalkynyl, C₃-C₆ halocycloalkyl, halogen, CN, NO₂, C₁-C₄        alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,        C₁-C₄ alkylsulfonyl, C₁-C₄ alkylamino, C₂-C₈ dialkylamino, C₃-C₆        cycloalkylamino, (C₁-C₄ alkyl)(C₃-C₆ cycloalkyl)amino, C₂-C₄        alkylcarbonyl, C₂-C₆ alkoxycarbonyl, C₂-C₆ alkylaminocarbonyl,        C₃-C₈ dialkylaminocarbonyl or C₃-C₆ trialkylsilyl;    -   R⁴ is H or an optionally substituted carbon moiety,    -   Z is N or CR⁵;    -   R⁵ is H or R³; and    -   n is an integer selected from 0 to 3.        One skilled in the art will recognize that Formula Ia is a        subgenus of Formula I, and Formula IIa is subgenus of Formula        II.

While a wide range of optionally substituted carbon moieties as alreadydescribed are useful as R⁴ in esters of Formula Ia for the method ofScheme 2, commonly R⁴ is a radical containing up to 18 carbon atoms andselected from alkyl, alkenyl and alkynyl; and benzyl and phenyl, eachoptionally substituted with alkyl and halogen. Most preferably R⁴ isC₁-C₄ alkyl.

Of note is the method shown in Scheme 2 wherein Z is N, n is 1 and R³ isCl or Br and is located at the 3-position. Also of note is the methodshown in Scheme 2 wherein X² is halogen or OS(O)₂R¹, particularly whereR¹ is methyl, phenyl or 4-methylphenyl. Also of note is the method shownin Scheme 2 wherein X¹ is Br or Cl and more particularly X¹ is Br. Ofparticular note is the method shown in Scheme 2 wherein X¹ is Br, X² isCl or OS(O)_(m)R¹, m is 2, and R¹ is phenyl or 4-methylphenyl.

When a basic functionality is present in the compound of Formula IIa(e.g., Z is N and/or R³ is alkylamino, dialkylamino, cycloalkylamino or(alkyl)(cycloalkyl)amino) typically more than one equivalent of HX¹ isneeded for satisfactory conversion even when X² is OS(O)_(m)R¹ orOP(O)_(p)(OR²)₂. When Z is N, R³ is other than alkylamino, dialkylamino,cycloalkylamino and (alkyl)(cycloalkyl)amino), and X² is S(O)₂R¹ inFormula IIa, excellent conversion is obtained using as little as 1.5 to2 equivalents of HX¹.

Starting compounds of Formula II wherein X² is halogen can be preparedfrom corresponding compounds of Formula 1 as shown in Scheme 3

-   -   wherein X² is halogen and L, R and k are as previously defined.        Treatment of a compound of Formula 1 with a halogenating        reagent, usually in the presence of a solvent, affords the        corresponding halo compound of Formula II. Halogenating reagents        that can be used include phosphorus oxyhalides, phosphorus        trihalides, phosphorus pentahalides, thionyl chloride,        dihalotrialkylphosphoranes, dihalodiphenylphosphoranes, oxalyl        chloride, phosgene, sulfur tetrafluoride and        (diethylamino)sulfur trifluoride. Preferred are phosphorus        oxyhalides and phosphorus pentahalides. To obtain complete        conversion, at least 0.33 equivalents of phosphorus oxyhalide        versus the compound of Formula 1 (i.e. the mole ratio of        phosphorus oxyhalide to Formula 1 is at least 0.33) should be        used, preferably between about 0.33 and 1.2 equivalents. To        obtain complete conversion, at least 0.20 equivalents of        phosphorus pentahalide versus the compound of Formula 1 should        be used, preferably between about 0.20 and 1.0 equivalents.        Typical solvents for this halogenation include halogenated        alkanes, such as dichloromethane, chloroform, chlorobutane and        the like, aromatic solvents, such as benzene, xylene,        chlorobenzene and the like, ethers, such as tetrahydrofuran,        p-dioxane, diethyl ether, and the like, and polar aprotic        solvents such as acetonitrile, N,N-dimethylformamide, and the        like. Optionally, an organic base, such as triethylamine,        pyridine, N,N-dimethylaniline or the like, can be added.        Addition of a catalyst, such as N,N-dimethylformamide, is also        an option. Preferred is the process in which the solvent is        acetonitrile and a base is absent. Typically, neither a base nor        a catalyst is required when acetonitrile solvent is used. The        preferred process is conducted by mixing the compound of Formula        1 in acetonitrile. The halogenating reagent is then added over a        convenient time, and the mixture is then held at the desired        temperature until the reaction is complete. The reaction        temperature is typically between about 20° C. and the boiling        point of acetonitrile, and the reaction time is typically less        than 2 hours. The reaction mass is then neutralized with an        inorganic base, such as sodium bicarbonate, sodium hydroxide and        the like, or an organic base, such as sodium acetate. The        desired product, a compound of Formula II, can be isolated by        methods known to those skilled in the art, including extraction,        crystallization and distillation.

As shown in Scheme 4, starting compounds of Formula II wherein R¹ is aOS(O)_(m)R¹ or OP(O)_(p)(OR²)₂ can likewise be prepared fromcorresponding compounds of Formula 1 by contacting with X³S(O)_(m)R¹ (2)or X³P(O)_(p)(OR²)₂ (3), respectively, wherein X³ is a nucleophilicreaction leaving group. Halides such as Cl are particularly useful forX³. Also useful for X³S(O)_(m)R¹ is X³ being OS(O)_(m)R¹ (i.e. Formula 2is R¹S(O)_(m)OS(O)_(m)R¹); X³ being OS(O)_(m)R¹ is particularly usefulwhen R¹ is CF₃. In view of synthetic accessibility and relatively lowcost, X³ being Cl is generally preferred.

-   -   wherein X² is OS(O)_(m)R¹ or OP(O)_(p)(OR²)₂, X³ is a leaving        group, and L, R, R¹, k, m and p are as previously defined.        In this method, the compound of Formula 1 is contacted with a        compound of Formula 2 (for X² being OS(O)_(m)R¹) or Formula 3        (for X² being OP(O)_(p)(OR²)₂), typically in the presence of a        solvent and a base. Suitable solvents include dichloromethane,        tetrahydrofuran, acetonitrile and the like. Suitable bases        include tertiary amines (e.g., triethylamine,        N,N-diisopropylethylamine) and ionic bases such as potassium        carbonate and the like. A tertiary amine is preferred as the        base. At least one of equivalent (preferably a small excess,        e.g., 5-100%) of the compound of Formula 2 or Formula 3 and the        base relative to the compound Formula 1 is generally used to        give complete conversion. The reaction is typically conducted at        a temperature between about −50° C. and the boiling point of the        solvent, more commonly between about 0° C. and ambient        temperature (i.e. about 15 to 30° C.). The reaction is typically        complete within a couple hours to several days; the progress of        the reaction can by monitored by such techniques known to those        skilled in the art as thin layer chromatography and analysis of        the ¹H NMR spectrum. The reaction mixture is then worked up,        such as by washing with water, drying the organic phase and        evaporating the solvent. The desired product, a compound of        Formula II, can be isolated by methods known to those skilled in        the art, including extraction, crystallization and distillation.

As Formula IIa is a subgenus of Formula II, compounds of Formula IIa canbe prepared from corresponding compounds of Formula Ia, which is asubgenus of Formula 1, by the methods already described for Schemes 3and 4.

-   -   wherein R³, R⁴, Z and n are as defined for Formula IIa.

Compounds of Formula 1 can be prepared by the great variety of modernsynthetic methodologies known to those skilled in the art. For example,compounds of Formula 1a can be prepared from compounds of Formulae 4 and5 as outlined in Scheme 5.

-   -   wherein R³, R⁴, Z and n are as defined for Formula IIa.        In this method, a hydrazine compound of Formula 4 is contacted        with a compound of Formula 5 (a fumarate ester or maleate ester        or a mixture thereof may be used) in the presence of a base and        a solvent. The base is typically a metal alkoxide salt, such as        sodium methoxide, potassium methoxide, sodium ethoxide,        potassium ethoxide, potassium tert-butoxide, lithium        tert-butoxide, and the like. Greater than 0.5 equivalents of        base versus the compound of Formula 4 should be used, preferably        between 0.9 and 1.3 equivalents. Greater than 1.0 equivalents of        the compound of Formula 5 should be used, preferably between 1.0        to 1.3 equivalents. Polar protic and polar aprotic organic        solvents can be used, such as alcohols, acetonitrile,        tetrahydrofuran, NW-dimethylformamide, dimethyl sulfoxide and        the like. Preferred solvents are alcohols such as methanol and        ethanol. It is especially preferred that the alcohol be the same        as that making up the fumarate or maleate ester and the alkoxide        base. The reaction is typically conducted by mixing the compound        of Formula 4 and the base in the solvent. The mixture can be        heated or cooled to a desired temperature and the compound of        Formula 5 added over a period of time. Typically reaction        temperatures are between 0° C. and the boiling point of the        solvent used. The reaction may be conducted under greater than        atmospheric pressure in order to increase the boiling point of        the solvent. Temperatures between about 30 and 90° C. are        generally preferred. The addition time can be as quick as heat        transfer allows. Typical addition times are between 1 minute and        2 hours. Optimum reaction temperature and addition time vary        depending upon the identities of the compounds of Formula 4 and        Formula 5. After addition, the reaction mixture can be held for        a time at the reaction temperature. Depending upon the reaction        temperature, the required hold time may be from 0 to 2 hours.        Typical hold times are 10 to 60 minutes. The reaction mass then        can be acidified by adding an organic acid, such as acetic acid        and the like, or an inorganic acid, such as hydrochloric acid,        sulfuric acid and the like. Depending on the reaction conditions        and the means of isolation, the —CO₂R⁴ function on the compound        of Formula 1a may be hydrolyzed to —CO₂H; for example, the        presence of water in the reaction mixture can promote such        hydrolysis. If the carboxylic acid (—CO₂H) is formed, it can be        converted back to —CO₂R⁴ wherein R⁴ is, for example, C₁-C₄ alkyl        using esterification methods well-known in the art The desired        product, a compound of Formula 1a, can be isolated by methods        known to those skilled in the art, such as crystallization,        extraction or distillation.

It is believed that one skilled in the art using the precedingdescription can utilize the present invention to its fullest extent. Thefollowing Examples are, therefore, to be construed as merelyillustrative, and not limiting of the disclosure in any way whatsoever.Steps in the following Examples illustrate a procedure for each step inan overall synthetic transformation, and the starting material for eachstep may not have necessarily been prepared by a particular preparativerun whose procedure is described in other Examples or Steps. Percentagesare by weight except for chromatographic solvent mixtures or whereotherwise indicated. Parts and percentages for chromatographic solventmixtures are by volume unless otherwise indicated. ¹H NMR spectra arereported in ppm downfield from tetramethylsilane; “s” means singlet, “d”means doublet, “t” means triplet, “q” means quartet, “m” meansmultiplet, “dd” means doublet of doublets, “dt” means doublet oftriplets, and “br s” means broad singlet.

EXAMPLE 1 Preparation of ethyl3-bromo-1(3-chloro-2-pyridinyl)4,5-dihydro-1H-pyrazole-5-carboxylate byReplacement of Chlorine with Bromine

Step A: Preparation of ethyl2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidine-carboxylate

A 2-L four-necked flask equipped with a mechanical stirrer, thermometer,addition funnel, reflux condenser, and nitrogen inlet was charged withabsolute ethanol (250 mL) and an ethanolic solution of sodium ethoxide(21%, 190 mL, 0.504 mol). The mixture was heated to reflux at about 83°C. It was then treated with 3-chloro-2(1H)-pyridinone hydrazone (68.0 g,0.474 mol). The mixture was re-heated to reflux over a period of 5minutes. The yellow slurry was then treated dropwise with diethylmaleate (88.0 mL, 0.544 mol) over a period of 5 minutes. The reflux rateincreased markedly during the addition. By the end of the addition allof the starting material had dissolved. The resulting orange-redsolution was held at reflux for 10 minutes. After being cooled to 65°C., the reaction mixture was treated with glacial acetic acid (50.0 mL,0.873 mol). A precipitate formed. The mixture was diluted with water(650 mL), causing the precipitate to dissolve. The orange solution wascooled in an ice bath. Product began to precipitate at 28° C. The slurrywas held at about 2° C. for 2 hours. The product was isolated viafiltration, washed with aqueous ethanol (40%, 3×50 mL), and thenair-dried on the filter for about 1 hour. The title product compound wasobtained as a highly crystalline, light orange powder (70.3 g, 55%yield). No significant impurities were observed by ¹H NMR.

¹H NMR (DMSO-d₆) δ 1.22 (t, 3H), 2.35 (d, 1H), 2.91 (dd, 1H), 4.20 (q,2H, 4.84 (d, 1H), 7.20 (dd, 1H), 7.92 (d, 1H), 8.27 (d, 1H), 10.18 (s,1H).

Step B: Preparation of ethyl3-chloro-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate

To a 2-L four-necked flask equipped with a mechanical stirrer,thermometer, reflux condenser, and nitrogen inlet was chargedacetonitrile (1000 mL), ethyl2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. theproduct of Step A) (91.0 g, 0.337 mol) and phosphorus oxychloride (35.0mL, 0.375 mol). Upon adding the phosphorus oxychloride, the mixtureself-heated from 22 to 25° C. and a precipitate formed. The light-yellowslurry was heated to reflux at 83° C. over a period of 35 minutes,whereupon the precipitate dissolved. The resulting orange solution washeld at reflux for 45 minutes, whereupon it had become black-green. Thereflux condenser was replaced with a distillation head, and 650 mL ofsolvent was removed by distillation. A second 2-L four-necked flaskequipped with a mechanical stirrer was charged with sodium bicarbonate(130 g, 1.55 mol) and water (400 mL). The concentrated reaction mixturewas added to the sodium bicarbonate slurry over a period of 15 minutes.The resulting, two-phase mixture was stirred vigorously for 20 minutes,at which time gas evolution had ceased. The mixture was diluted withdichloromethane (250 mL) and then was stirred for 50 minutes. Themixture was treated with Celite® 545 diatomaceous earth filter aid (11g) and then filtered to remove a black, tarry substance that inhibitedphase separation. Since the filtrate was slow to separate into distinctphases, it was diluted with dichloromethane (200 mL) and water (200 mL)and treated with more Celite® 545 (15 g). The mixture was filtered, andthe filtrate was transferred to a separatory funnel. The heavier, deepgreen organic layer was separated. A rag layer (50 mL) was refilteredand then added to the organic layer. The organic solution (800 mL) wastreated with magnesium sulfate (30 g) and silica gel (12 g), and theslurry was stirred magnetically for 30 minutes. The slurry was filteredto remove the magnesium sulfate and silica gel, which had become deepblue-green. The filter cake was washed with dichloromethane (100 mL).The filtrate was concentrated on a rotary evaporator. The productconsisted of dark amber oil (92.0 g, 93% yield). The only appreciableimpurities observed by ¹H NMR were 1% starting material and 0.7%acetonitrile.

¹H NMR (DMSOd-₆) δ 1.15 (t, 3H), 3.26 (dd, 1H), 3.58 (dd, 1H), 4.11 (q,2H), 5.25 (dd, 1H), 7.00 (dd, 1H), 7.84 (d, 1H), 8.12 (d, 1H).

Step C: Preparation of ethyl3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate

Hydrogen bromide was passed through a solution of ethyl3-chloro-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate(i.e. product of Step B) (8.45 g, 29.3 mmol) in dibromomethane (85 mL).After 90 minutes the gas flow was terminated, and the reaction mixturewas washed with aqueous sodium bicarbonate solution (100 mL). Theorganic phase was dried and evaporated under reduced pressure to givethe title product as an oil (9.7 g, 99% yield), which crystallized onstanding.

¹H NMR (CDCl₃) δ 1.19 (t, 3H), 3.24 (½ of AB in ABX pattern, J=9.3, 17.3Hz, 1H) 3.44 (½ of AB in ABX pattern, J=11.7, 17.3 Hz, 1H), 4.18 (q,2H), 5.25 (X of ABX 1H, J=9.3, 11.9 Hz), 6.85 (dd, J=4.7, 7.7 Hz, 1H),7.65 (dd, J=1.6, 7.8 Hz, 1H), 8.07 (dd, J=1.6, 4.8 Hz, 1H).

EXAMPLE 2 Preparation of ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5dihydro-1H-pyrazole-5-carboxylate by Replacement of Tosylate withBromine

Step A: Preparation of ethyl1-(3-chloro-2-pyridinyl)-4,5-dihydro-3-[[(4-methyl-phenyl)sulfonyl]oxy]-1H-pyrazole-5-carboxylate

Triethylamine (3.75 g, 37.1 mmol) was added dropwise to a mixture ofethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. theproduct of Example 1, Step A) (10.0 g, 37.1 mmol) and p-toluenesulfonylchloride (7.07 g, 37.1 mmol) in dichloromethane (100 mL) at 0° C.Further portions of p-toluenesulfonyl chloride (0.35 g, 1.83 mmol) andtriethylamine (0.19 g, 1.88 mmol) were added. The reaction mixture wasthen allowed to warm to room temperature and was stirred overnight. Themixture was then diluted with dichloromethane (200 mL) and washed withwater (3×70 mL). The organic phase was dried and evaporated to leave thetitle product as an oil (13.7 g, 87% yield), which slowly formedcrystals. Product recrystallized from ethyl acetate/hexanes melted at99.5-100° C.

IR (nujol): 1740, 1638, 1576, 1446, 1343, 1296, 1228, 1191, 1178, 1084,1027, 948, 969, 868,845 cm^(−1.) ¹H NMR (CDCl₃) δ 1.19 (t, 3H), 2.45 (s,3H), 3.12 (½ of AB in ABX pattern, J=17.3, 9 Hz, 1H), 3.33 (½ of AB inABX pattern, J=17.5, 11.8 Hz, 1H), 4.16 (q, 2H), 5.72 (X of ABX, J=9,11.8 Hz, 1H), 6.79 (dd, J=4.6, 7.7 Hz, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.56(dd, J=1.6, 7.8 Hz, 1H), 7.95 (d, J=8.4 Hz, 2H), 8.01 (dd, J=1.4, 4.6Hz, 1H).

Step B: Preparation of ethyl3-bromo-1-(3-chloro-2-pyridinyl)4,5-dihydro-1H-pyrazole-5-carboxylate

Hydrogen bromide was passed through a solution of ethyl1-(3-chloro-2-pyridinyl)-4,5-dihydro-3-[[(4-methylphenyl)sulfonyl]oxy]-1H-pyrazole-5-carboxylate(i.e. product of Step A) (5 g, 11.8 mmol) in dibromomethane (50 mL).After about 60 minutes the gas flow was terminated, and the reactionmixture was washed with aqueous sodium bicarbonate solution (50 mL). Theorganic phase was dried and evaporated under reduced pressure to givethe title product as an oil (3.92 g, 100% yield), which crystallized onstanding. The ¹H NMR spectrum of the product was the same as reportedfor the product of Example 1, Step C.

EXAMPLE 3 Preparation of ethyl3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylateby Replacement of Benzenesulfonate with Bromine

Step A: Preparation of ethyl1-(3-chloro-2-pyridinyl)-4,5-dihydro-3-[(phenyl-sulfonyl)oxy]-1H-pyrazole-5-carboxylate

Triethylamine (1.85 g, 18.5 mmol) was added dropwise over 1 h to amixture of ethyl2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. theproduct of Example 1, Step A) (5.0 g, 18.5 mmol) and benzenesulfonylchloride (3.27 g, 18.5 mmol) in dichloromethane (20 mL) at 0° C. Thetemperature was not allowed to exceed 1° C. After stirring the reactionmixture for an additional 2 h, a further portion of benzenesulfonylchloride (0.5 g, 1.85 mmol) was added. Then a further portion oftriethylamine (0.187 g, 1.85 mmol) was added dropwise to the mixture.After stirring for 0.5 h more, the mixture was partitioned between water(100 mL) and dichloromethane (100 mL). The organic layer was dried(MgSO₄) and evaporated to provide the title product as an orange solid(7.18 g, 94% yield). Product recrystallized from ethyl acetate/hexanesmelted at 84-85° C.

IR (nujol): 1737, 1639, 1576, 1448, 1385, 1346, 1302, 1233, 1211, 1188,1176, 1088, 1032, 944, 910, 868, 846 cm^(−1.) ¹H NMR (CDCl₃) δ 1.19 (t,3H), 3.15 (1/2 of the AB in ABX pattern, J=8.8, 17.3 Hz, 1H), 3.36 (1/2of the AB in ABX pattern, J=11.8, 17.3 Hz, 1H), 4.17 (q, 2H), 5.23 (X ofABX, J=8.8, 11.8 Hz, 1H), 6.78 (dd, J=2.8, 4.8 Hz, 1H), 7.71-7.55 (m,4H), 8.01 (dd, J=1.6, 4.6 Hz, 2H), 8.08 (dd, J=1.0, 2.6 Hz, 2H).

Step B: Preparation of ethyl3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate

A solution of ethyl1-(3-chloro-2-pyridinyl)-4,5-dihydro-3-[(phenylsulfonyl)oxy]-1H-pyrazole-5-carboxylate(i.e. the product of Step A)(1.0 g, 2.44 mmol) in acetic acid (4 mL) wasadded to a solution of hydrogen bromide in acetic acid (33%, 1.2 g, 4.89mmol). After about 1 h the reaction mixture was added to saturatedaqueous sodium hydrogen carbonate solution (100 mL). The mixture wasthen extracted with ethyl acetate (2×50 mL), and the combined extractswere dried (MgSO₄) and evaporated to provide the title product as an oil(0.69 g, 85% yield), which slowly crystallized. The ¹H NMR spectrum wasthe same as reported for the product of Example 1, Step C.

By the procedures described herein together with methods known in theart, the compounds of Formula II can be converted to compounds ofFormula I as illustrated for Formulae Ia and Ha in Table 1. Thefollowing abbreviations are used in the Table: t is tertiary, s issecondary, n is normal, i is iso, Me is methyl, Et is ethyl, Pr ispropyl, i-Pr is isopropyl, t-Bu is tertiary butyl and Ph is phenyl.

TABLE 1

X¹ is Br, X² is OS(O)₂Ph Z is N Z is CH Z is CCl Z is CBr R³ R⁴ R³ R⁴ R³R⁴ R³ R⁴ R³ R⁴ R³ R⁴ R³ R⁴ R³ R⁴ 3-Cl H 3-Br H 3-Cl H 3-Br H 3-Cl H 3-BrH 3-Cl H 3-Br H 3-Cl Me 3-Br Me 3-Cl Me 3-Br Me 3-Cl Me 3-Br Me 3-Cl Me3-Br Me 3-Cl Et 3-Br Et 3-Cl Et 3-Br Et 3-Cl Et 3-Br Et 3-Cl Et 3-Br Et3-Cl n-Pr 3-Br n-Pr 3-Cl n-Pr 3-Br n-Pr 3-Cl n-Pr 3-Br n-Pr 3-Cl n-Pr3-Br n-Pr 3-Cl i-Pr 3-Br i-Pr 3-Cl i-Pr 3-Br i-Pr 3-Cl i-Pr 3-Br i-Pr3-Cl i-Pr 3-Br i-Pr 3-Cl n-Bu 3-Br n-Bu 3-Cl n-Bu 3-Br n-Bu 3-Cl n-Bu3-Br n-Bu 3-Cl n-Bu 3-Br n-Bu 3-Cl i-Bu 3-Br i-Bu 3-Cl i-Bu 3-Br i-Bu3-Cl i-Bu 3-Br i-Bu 3-Cl i-Bu 3-Br i-Bu 3-Cl s-Bu 3-Br s-Bu 3-Cl s-Bu3-Br s-Bu 3-Cl s-Bu 3-Br s-Bu 3-Cl s-Bu 3-Br s-Bu 3-Cl t-Bu 3-Br t-Bu3-Cl t-Bu 3-Br t-Bu 3-Cl t-Bu 3-Br t-Bu 3-Cl t-Bu 3-Br t-Bu X¹ is Br; X²is OS(O)₂Ph-4-Me Z is N Z is CH Z is CCl Z is CBr R³ R⁴ R³ R⁴ R³ R⁴ R³R⁴ R³ R⁴ R³ R⁴ R³ R⁴ R³ R⁴ 3-Cl H 3-Br H 3-Cl H 3-Br H 3-Cl H 3-Br H3-Cl H 3-Br H 3-Cl Me 3-Br Me 3-Cl Me 3-Br Me 3-Cl Me 3-Br Me 3-Cl Me3-Br Me 3-Cl Et 3-Br Et 3-Cl Et 3-Br Et 3-Cl Et 3-Br Et 3-Cl Et 3-Br Et3-Cl n-Pr 3-Br n-Pr 3-Cl n-Pr 3-Br n-Pr 3-Cl n-Pr 3-Br n-Pr 3-Cl n-Pr3-Br n-Pr 3-Cl i-Pr 3-Br i-Pr 3-Cl i-Pr 3-Br i-Pr 3-Cl i-Pr 3-Br i-Pr3-Cl i-Pr 3-Br i-Pr 3-Cl n-Bu 3-Br n-Bu 3-Cl n-Bu 3-Br n-Bu 3-Cl n-Bu3-Br n-Bu 3-Cl n-Bu 3-Br n-Bu 3-Cl i-Bu 3-Br i-Bu 3-Cl i-Bu 3-Br i-Bu3-Cl i-Bu 3-Br i-Bu 3-Cl i-Bu 3-Br i-Bu 3-Cl s-Bu 3-Br s-Bu 3-Cl s-Bu3-Br s-Bu 3-Cl s-Bu 3-Br s-Bu 3-Cl s-Bu 3-Br s-Bu 3-Cl t-Bu 3-Br t-Bu3-Cl t-Bu 3-Br t-Bu 3-Cl t-Bu 3-Br t-Bu 3-Cl t-Bu 3-Br t-Bu X¹ is Br, X²is OS(O)₂Me Z is N Z is CH Z is CCl Z is CBr R³ R⁴ R³ R⁴ R³ R⁴ R³ R⁴ R³R⁴ R³ R⁴ R³ R⁴ R³ R⁴ 3-Cl H 3-Br H 3-Cl H 3-Br H 3-Cl H 3-Br H 3-Cl H3-Br H 3-Cl Me 3-Br Me 3-Cl Me 3-Br Me 3-Cl Me 3-Br Me 3-Cl Me 3-Br Me3-Cl Et 3-Br Et 3-Cl Et 3-Br Et 3-Cl Et 3-Br Et 3-Cl Et 3-Br Et 3-Cln-Pr 3-Br n-Pr 3-Cl n-Pr 3-Br n-Pr 3-Cl n-Pr 3-Br n-Pr 3-Cl n-Pr 3-Brn-Pr 3-Cl i-Pr 3-Br i-Pr 3-Cl i-Pr 3-Br i-Pr 3-Cl i-Pr 3-Br i-Pr 3-Cli-Pr 3-Br i-Pr 3-Cl n-Bu 3-Br n-Bu 3-Cl n-Bu 3-Br n-Bu 3-Cl n-Bu 3-Brn-Bu 3-Cl n-Bu 3-Br n-Bu 3-Cl i-Bu 3-Br i-Bu 3-Cl i-Bu 3-Br i-Bu 3-Cli-Bu 3-Br i-Bu 3-Cl i-Bu 3-Br i-Bu 3-Cl s-Bu 3-Br s-Bu 3-Cl s-Bu 3-Brs-Bu 3-Cl s-Bu 3-Br s-Bu 3-Cl s-Bu 3-Br s-Bu 3-Cl t-Bu 3-Br t-Bu 3-Clt-Bu 3-Br t-Bu 3-Cl t-Bu 3-Br t-Bu 3-Cl t-Bu 3-Br t-Bu X¹ is Br; X² isCl Z is N Z is CH Z is CCl Z is CBr R³ R⁴ R³ R⁴ R³ R⁴ R³ R⁴ R³ R⁴ R³ R⁴R³ R⁴ R³ R⁴ 3-Cl H 3-Br H 3-Cl H 3-Br H 3-Cl H 3-Br H 3-Cl H 3-Br H 3-ClMe 3-Br Me 3-Cl Me 3-Br Me 3-Cl Me 3-Br Me 3-Cl Me 3-Br Me 3-Cl Et 3-BrEt 3-Cl Et 3-Br Et 3-Cl Et 3-Br Et 3-Cl Et 3-Br Et 3-Cl n-Pr 3-Br n-Pr3-Cl n-Pr 3-Br n-Pr 3-Cl n-Pr 3-Br n-Pr 3-Cl n-Pr 3-Br n-Pr 3-Cl i-Pr3-Br i-Pr 3-Cl i-Pr 3-Br i-Pr 3-Cl i-Pr 3-Br i-Pr 3-Cl i-Pr 3-Br i-Pr3-Cl n-Bu 3-Br n-Bu 3-Cl n-Bu 3-Br n-Bu 3-Cl n-Bu 3-Br n-Bu 3-Cl n-Bu3-Br n-Bu 3-Cl i-Bu 3-Br i-Bu 3-Cl i-Bu 3-Br i-Bu 3-Cl i-Bu 3-Br i-Bu3-Cl i-Bu 3-Br i-Bu 3-Cl s-Bu 3-Br s-Bu 3-Cl s-Bu 3-Br s-Bu 3-Cl s-Bu3-Br s-Bu 3-Cl s-Bu 3-Br s-Bu 3-Cl t-Bu 3-Br t-Bu 3-Cl t-Bu 3-Br t-Bu3-Cl t-Bu 3-Br t-Bu 3-Cl t-Bu 3-Br t-Bu X¹ is Cl; X² is OS(O)₂Ph-4-Me Zis N Z is CH Z is CCl Z is CBr R³ R⁴ R³ R⁴ R³ R⁴ R³ R⁴ R³ R⁴ R³ R⁴ R³ R⁴R³ R⁴ 3-Cl H 3-Br H 3-Cl H 3-Br H 3-Cl H 3-Br H 3-Cl H 3-Br H 3-Cl Me3-Br Me 3-Cl Me 3-Br Me 3-Cl Me 3-Br Me 3-Cl Me 3-Br Me 3-Cl Et 3-Br Et3-Cl Et 3-Br Et 3-Cl Et 3-Br Et 3-Cl Et 3-Br Et 3-Cl n-Pr 3-Br n-Pr 3-Cln-Pr 3-Br n-Pr 3-Cl n-Pr 3-Br n-Pr 3-Cl n-Pr 3-Br n-Pr 3-Cl i-Pr 3-Bri-Pr 3-Cl i-Pr 3-Br i-Pr 3-Cl i-Pr 3-Br i-Pr 3-Cl i-Pr 3-Br i-Pr 3-Cln-Bu 3-Br n-Bu 3-Cl n-Bu 3-Br n-Bu 3-Cl n-Bu 3-Br n-Bu 3-Cl n-Bu 3-Brn-Bu 3-Cl i-Bu 3-Br i-Bu 3-Cl i-Bu 3-Br i-Bu 3-Cl i-Bu 3-Br i-Bu 3-Cli-Bu 3-Br i-Bu 3-Cl s-Bu 3-Br s-Bu 3-Cl s-Bu 3-Br s-Bu 3-Cl s-Bu 3-Brs-Bu 3-Cl s-Bu 3-Br s-Bu 3-Cl t-Bu 3-Br t-Bu 3-Cl t-Bu 3-Br t-Bu 3-Clt-Bu 3-Br t-Bu 3-Cl t-Bu 3-Br t-Bu X¹ is Br; X² is OS(O)₂Me R³ R⁴ Z R³R⁴ Z R³ R⁴ Z R³ R⁴ Z 3-Me H N 4-Me H CH 3-Br H N 3-CF₃ H N 5-Cl Me CH3-OEt Me N 4-I Me CH 5-CF₂H Me CH 4-n-Bu Et N 2-OCF₃ Et N 3-CN Et CH6-CH₃ Et N 5-NMe₂ n-Pr CH 3-cyclo-Pr n-Pr CH 3-NO₂ n-Pr CH 3-CH₂CF₃ n-PrCH 3-OCH₂F i-Pr N H i-Pr N 3-S(O)₂CH₃ i-Pr CH 6-cyclohexyl i-Pr CH4-OCH₃ n-Bu CH 4-F n-Bu CCl 4-SCH₃ n-Bu CH 4-CH₂CH═CH₂ n-Bu CH X¹ is BrR³ R⁴ Z X² R³ R⁴ Z X² 3-Cl H N OS(O)₂Et 3-Cl H N OS(O)₂CF₃ 3-Br Me CHOS(O)Me 3-Br Me CH OS(O)₂-n-Bu 3-Cl Et N OP(O)(OMe)₂ 3-Cl Et NOP(O)(O-i-Pr)₂ 3-Br n-Pr CH OP(OMe)₂ 3-Br n-Pr CH OS(O)₂Ph-2,4,6-tri-Me3-Cl i-Pr N OP(O)(OEt)₂ 3-Cl i-Pr N OP(O)(OPh-4-Me)₂ 3-Br n-Bu CHOP(O)(OPh)₂ 3-Br n-Bu CH OS(O)₂Ph-4-Cl

The 3-halo-4,5-dihydro-1H-pyrazole preparation method of the presentinvention can be used to prepare a wide variety of compounds of FormulaI that are useful as intermediates for the preparation of cropprotection agents, pharmaceuticals and other fine chemicals. Exhibit 3lists examples of 3-halo-4,5-dihydro-1H-pyrazoles which can be preparedaccording to the method of the present invention from corresponding4,5-dihydro-1H-pyrazoles having OS(O)_(m)R¹ (e.g., OS(O)₂CH₃ orOS(O)₂Ph), OP(O)_(p)(OR²)₂ (e.g., OP(O)(OMe)₂) or a different halogensubstituent (e.g., Cl replacing Br, or Br replacing Cl), including3-halo-4,5-dihydro-1H-pyrazoles which are useful in the preparation ofproducts having fungicidal, herbicidal or plant growth regulant utility.These examples are to be construed as illustrative, but not limiting, ofthe diverse scope of applicability of the method of the presentinvention. Other compounds preparable according to the method of thepresent invention may be useful for the preparation of pharmaceuticalproducts, such as anti-inflammatories, allergy inhibitors,anti-convulsants, sedative agents, etc.

Among the compounds preparable according to the method of the presentinvention, compounds of Formula Ia are particularly useful for preparingcompounds of Formula III

wherein Z, X¹, R³ and n are defined as above; R⁶ is CH₃, F, Cl or Br; R⁷is F, Cl, Br, I or CF₃; R^(8a) is C₁-C₄ alkyl; and R^(8b) is H or CH₃.Preferably Z is N, n is 1, and R³ is Cl or Br and is at the 3-position.

Compounds of Formula III are useful as insecticides, as described, forexample, in PCT. Publication No. WO01/70671, published Sep. 27, 2001, aswell as in U.S. Patent Application 60/324,173, filed Sep. 21, 2001, U.S.Patent Application 60/323,941, filed Sep. 21, 2001 and U.S. PatentApplication 60/369,661, filed Apr. 2, 2002. The preparation of compoundsof Formula 8 and Formula III is described in U.S. Patent Application60/400,352, filed Jul. 31, 2002 [BA9308 US PRV], and U.S. PatentApplication 60/446,438, filed Feb. 11, 2003 [BA9308 US PRV1] and herebyincorporated herein in their entirety by reference; as well as in U.S.Patent Application 60/369,660, filed Apr. 2, 2002.

Compounds of Formula III can be prepared from corresponding compounds ofFormula Ia by the processes outlined in Schemes 6-9.

As illustrated in Scheme 6, a compound of Formula Ia is treated with anoxidizing agent optionally in the presence of acid.

-   -   wherein R³, R⁴, Z, X¹ and n are as previously defined for        Formula Ia.

A compound of Formula Ia wherein R⁴ is C₁-C₄ alkyl is preferred asstarting material for this step. The oxidizing agent can be hydrogenperoxide, organic peroxides, potassium persulfate, sodium persulfate,ammonium persulfate, potassium monopersulfate (e.g., Oxone®) orpotassium permanganate. To obtain complete conversion, at least oneequivalent of oxidizing agent versus the compound of Formula Ia shouldbe used, preferably from about one to two equivalents. This oxidation istypically carried out in the presence of a solvent. The solvent can bean ether, such as tetrahydrofuran p-dioxane and the like, an organicester, such as ethyl acetate, dimethyl carbonate and the like, or apolar aprotic organic such as N,N-dimethylformamide, acetonitrile andthe like. Acids suitable for use in the oxidation step include inorganicacids, such as suluric acid, phosphoric acid and the like, and organicacids, such as acetic acid, benzoic acid and the like. The acid, whenused, should be used in greater than 0.1 equivalents versus the compoundof Formula Ia. To obtain complete conversion, one to five equivalents ofacid can be used. For the compounds of Formula Ia wherein Z is CR⁵, thepreferred oxidant is hydrogen peroxide and the oxidation is preferablycarried out in the absence of acid. For the compounds of Formula Iawherein Z is N, the preferred oxidant is potassium persulfate and theoxidation is preferably carried out in the presence of sulfuric acid.The reaction can be carried out by mixing the compound of Formula Ia inthe desired solvent and, if used, the acid. The oxidant can then beadded at a convenient rate. The reaction temperature is typically variedfrom as low as about 0° C. up to the boiling point of the solvent inorder to obtain a reasonable reaction time to complete the reaction,preferably less than 8 hours. The desired product, a compound of Formula6 can be isolated by methods known to those skilled in the art,including extraction, chromatography, crystallization and distillation.

Carboxylic acid compounds of Formula 6 wherein R⁴ is H can be preparedby hydrolysis from corresponding ester compounds of Formula 6 wherein,for example, R⁴ is C₁-C₄ alkyl. Carboxylic ester compounds can beconverted to carboxylic acid compounds by numerous methods includingnucleophilic cleavage under anhydrous conditions or hydrolytic methodsinvolving the use of either acids or bases (see T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley &Sons, Inc., New York, 1991, pp. 224269 for a review of methods). Forcompounds of Formula 6, base-catalyzed hydrolytic methods are preferred.Suitable bases include alkali metal (such as lithium, sodium orpotassium) hydroxides. For example, the ester can be dissolved in amixture of water and an alcohol such as ethanol. Upon treatment withsodium hydroxide or potassium hydroxide, the ester is saponified toprovide the sodium or potassium salt of the carboxylic acid.Acidification with a strong acid, such as hydrochloric acid or sulfuricacid, yields the carboxylic acid of Formula 6 wherein R⁴ is H. Thecarboxylic acid can be isolated by methods known to those skilled in theart, including extraction, distillation and crystallization.

Coupling of a pyrazolecarboxylic acid of Formula 6 wherein R⁴ is H withan anthranilic acid of Formula 7 provides the benzoxazinone of Formula8. In Scheme 7, a benzoxazinone of Formula 8 is prepared directly viasequential addition of methanesulfonyl chloride in the presence of atertiary amine such as triethylamine or pyridine to a pyrazolecarboxylicacid of Formula 6 wherein R⁴ is H, followed by the addition of ananthranilic, acid of Formula 7, followed by a second addition oftertiary amine and methanesulfonyl chloride.

-   -   wherein R³, R⁶, R⁷, X¹, Z and n are as defined for Formula III.

This procedure generally affords good yields of the benzoxazinone.

Scheme 8 depicts an alternate preparation for benzoxazinones of Formula8 involving coupling of a pyrazole acid chloride of Formula 10 with anisatoic anhydride of Formula 9 to provide the Formula 8 benzoxazinonedirectly.

-   -   wherein R³, R⁶, R⁷, X¹, Z and n are as defined for Formula III.

Solvents such as pyridine or pyridine/acetonitrile are suitable for thisreaction. The acid chlorides of Formula 10 are available from thecorresponding acids of Formula 6 wherein R⁴ is H by known proceduressuch as chlorination with thionyl chloride or oxalyl chloride.

Compounds of Formula III can be prepared by the reaction ofbenzoxazinones of Formula 8 with C₁-C₄ alkylamines and (C₁-C₄alkyl)(methyl)amines of Formula 11 as outlined in Scheme 9.

-   -   wherein R³, R⁶, R⁷, R^(8a), R^(8b), X¹, Z and n are as        previously defined.

The reaction can be run neat or in a variety of suitable solventsincluding acetonitrile, tetrahydrofuran, diethyl ether, dichloromethaneor chloroform with optimum temperatures ranging from room temperature tothe reflux temperature of the solvent. The general reaction ofbenzoxazinones with amines to produce anthranilamides is well documentedin the chemical literature. For a review of benzoxazinone chemistry seeJakobsen et al., Biorganic and Medicinal Chemistry 2000, 8, 2095-2103and references cited within. See also Coppola, J. Heterocyclic Chemistry1999, 36, 563-588.

1. A method for preparing a 3-halo-4,5-dihydro-1H-pyrazole compound ofFormula I

wherein L is an optionally substituted carbon moiety; each R isindependently selected from optionally substituted carbon moieties; k isan integer from 0 to 4; and X¹ is halogen; comprising: contacting a4,5-dihydro-1H-pyrazole compound of Formula II

wherein X² is OS(O)_(m)R¹, OP(O)_(p)(OR²)₂ or a halogen other than X¹; mis 1 or 2; p is 0 or 1; R¹ is selected from alkyl and haloalkyl; andphenyl optionally substituted with from 1 to 3 substituents selectedfrom alkyl and halogen; and each R² is independently selected from alkyland haloalkyl; and phenyl optionally substituted with from 1 to 3substituents selected from alkyl and halogen; with a compound of theformula HX¹ in the presence of a suitable solvent.
 2. The method ofclaim 1 wherein m is 2 and p is
 1. 3. The method of claim 2 wherein X²is halogen or OS(O)_(m)R¹.
 4. The method of claim 3 wherein X² is Cl orOS(O)_(m)R¹ and R¹ is C₁-C₂ alkyl, phenyl or 4-methylphenyl.
 5. Themethod of claim 1 wherein X¹ is Cl or Br.
 6. The method of claim 1wherein the compound of Formula I is of Formula Ia

and the compound of Formula II is of Formula IIa

 wherein each R³ is independently C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl, C₃-C₆ cycloalkyl, C₁-C₄ haloalkyl, C₂-C₄ haloalkenyl, C₂-C₄haloalkynyl, C₃-C₆ halocycloalkyl, halogen, CN, NO₂, C₁-C₄ alkoxy, C₁-C₄haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl, C₁-C₄ alkylsulfonyl,C₁-C₄ alkylamino, C₂-C₈ dialkylamino, C₃-C₆ cycloalkylamino, (C₁-C₄alkyl)(C₃-C₆ cycloalkyl)amino, C₂-C₄ alkylcarbonyl, C₂-C₆alkoxycarbonyl, C₂-C₆ alkylaminocarbonyl, C₃-C₈ dialkylaminocarbonyl orC₃-C₆ trialkylsilyl; R⁴ is H or an optionally substituted carbon moiety;Z is N or CR⁵; R⁵ is H or R³; and n is an integer from 0 to
 3. 7. Themethod of claim 6 wherein R⁴ is C₁-C₄ alkyl.
 8. The method of claim 7wherein Z is N, n is 1, and R³ is Cl or Br and is at the 3-position. 9.The method of claim 7 wherein X¹ is Br, X² is Cl or OS(O)_(m)R¹, m is 2,and R¹ is phenyl or 4-methylphenyl.
 10. A method of preparing a compoundof Formula III

wherein X¹ is halogen; each R³ is independently C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₁-C₄ haloalkyl, C₂-C₄haloalkenyl, C₂-C₄ haloalkynyl, C₃-C₆ halocycloalkyl, halogen, CN, NO₂,C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ alkylthio, C₁-C₄ alkylsulfinyl,C₁-C₄ alkylsulfonyl, C₁-C₄ alkylamino, C₂-C₈ dialkylamino, C₃-C₆cycloalkylamino, (C₁-C₄ alkyl)(C₃-C₆ cycloalkyl)amino, C₂-C₄alkylcarbonyl, C₂-C₆ alkoxycarbonyl, C₂-C₆ alkylaminocarbonyl, C₃-C₈dialkylaminocarbonyl or C₃-C₆ trialkylsilyl; Z is N or CR⁵; R⁵ is H orR³; R⁶ is CH₃, F, Cl or Br; R⁷ is F, Cl, Br, I or CF₃; R^(8a) is C₁-C₄alkyl; R^(8b) is H or CH₃; and n is an integer from 0 to 3 using acompound of Formula Ia

wherein R⁴ is H or an optionally substituted carbon moiety, by forexample, (1) providing a compound of Formula 6 wherein R₄ is H by (a)oxidizing a compound of Formula Ia to form a compound of Formula 6;

(b) if R₄ for the compound of Formula 6 formed in (a) is an optionallysubstituted carbon moiety, hydrolyzing said compound of Formula 6 formedin (a); (2) providing a compound of Formula 8 either by (c) couplingsaid compound of Formula (6) wherein R₄ is H provided in (1) with acompound of Formula 7; or by

(d1) chlorinating said compound of Formula 6 wherein R₄ is H provided in(1) to form a compound of Formula 10; and (d2) coupling said compound ofFormula 10 with a compound of Formula 9; and

(3) reacting said compound of Formula 8 provided in (2) with a compoundof Formula 11;R^(8a)(R^(8b))NH  (11);  charactarized by: preparing said copound ofFormula Ia by the method of claim
 6. 11. The method of claim 10 whereinR⁴ in the compound of Formula Ia is C₁-C₄ alkyl.
 12. The method of claim11 wherein Z is N, n is 1, and R³ is Cl or Br and is at the 3-position.13. The method of claim 11 wherein X¹ is Br, X² is Cl or OS(O)_(m)R¹, mis 2, and R¹ is phenyl or 4-methylphenyl.